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Inhibition of KDM6B prevents osteoarthritis by blocking growth plate-like H3K27me3 loss in bivalent genes

Science China Life Sciences 2025年第5期68卷 1423-1436页

作者： Hao Du Yao Zhang Xi Yu Xuanhe You Diwei Wu Ze Du Yongrui Cai Zhenyu Luo Hanpeng Lu Zhixin Liao Bi-Sen Ding Ya Zhao Yan Wang Ke Xiao Fan Yang Fangji Gan Ning Ning Jiancheng Zeng Peiliang Shi Zongke Zhou Shishu Huang Department of Orthopedic Surgery and Orthopedic Research Institute West China HospitalSichuan University Rehabilitation Medicine Center West China HospitalSichuan University Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE State Key Laboratory of BiotherapyWest China Second University HospitalSichuan University Institute of Translational Medicine Medical CollegeYangzhou University Jiangsu Key Laboratory of Experimental & Translational Non-coding RNA Research College of Animal Science and Technology Sichuan Agricultural University Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province Sichuan Agricultural University Department of Lower Limb Surgery of Sichuan Province Orthopedic Hospital Central Laboratory of Sichuan Province Orthopedic Hospital Brain Cognition and Brain Disease Institute (BCBDI) Shenzhen Institute of Advanced TechnologyChinese Academy of Sciences (CAS)Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions School of Mechanical Engineering Sichuan University Gem Pharmatech (Chengdu) Co. Ltd.

Osteoarthritis(OA) is the most prevalent joint disorder occurring with articular cartilage degradation. It includes a switch from an articular to a growth plate chondrocyte phenotype. Here, we investigated the histone modification profiles and found significant H3K27me3 loss in OA, which led to disease-associated gene expression. Surprisingly, these genes were occupied by both H3K27me3 and H3K4me3 in normal chondrocytes, showing a poised bivalent state. Furthermore, we observed the derepression of similar bivalent genes in growth plate chondrocytes. Finally, a KDM6B inhibitor GSK-J4 prevented the H3K27me3 loss and cartilage damage in the rat OA model. Our results reveal an inherited bivalent epigenetic signature on developmental genes that makes articular chondrocytes prone to hypertrophy and contributes to a promising epigenetic therapy for OA.

关键词： osteoarthritis histone modifications H3K27me3 bivalency growth plate

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Quality Assessment of Domesticated Animal Genome Assemblies

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Bioinformatics and Biology Insights 2015年第Suppl 4期9S4卷 49-58页

作者： Seemann, Stefan E. Anthon, Christian Palasca, Oana Gorodkin, Jan Center for non-coding RNA in Technology and Health Department of Veterinary Clinical and Animal Sciences University of Copenhagen København Denmark

The era of high-throughput sequencing has made it relatively simple to sequence genomes and transcriptomes of individuals from many species. In order to analyze the resulting sequencing data, high-quality reference genome assemblies are required. However, this is still a major challenge, and many domesticated animal genomes still need to be sequenced deeper in order to produce high-quality assemblies. In the meanwhile, ironically, the extent to which rna seq and other next-generation data is produced frequently far exceeds that of the genomic sequence. Furthermore, basic comparative analysis is often affected by the lack of genomic sequence. Herein, we quantify the quality of the genome assemblies of 20 domesticated animals and related species by assessing a range of measurable parameters, and we show that there is a positive correlation between the fraction of mappable reads from rnaseq data and genome assembly quality. We rank the genomes by their assembly quality and discuss the implications for genotype analyses. © 2015, © 2015 SAGE Publications.

关键词： assembly quality domesticated animals genome assembly

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PTMD: A Database of Human Disease-associated Post-translational Modifications

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Genomics, Proteomics & Bioinformatics 2018年第4期16卷 244-251页

作者： Haodong Xu Yongbo Wang Shaofeng Lin Wankun Deng Di Peng Qinghua Cui Yu Xue Department of Bioinformatics & Systems Biology MOE Key Laboratory of Molecular Biophysics College of Life Science and Technology and the Collaborative Innovation Center for Biomedical Engineering Huazhong University of Science and Technology Department of Biomedical Informatics School of Basic Medical Sciences MOE Key Laboratory of Molecular Cardiovascular Sciences Center for Non-coding RNA Medicine Peking University

Various posttranslational modifications （PTMs） participate in nearly all aspects of biological processes by regulating protein functions, and aberrant states of PTMs are frequently implicated in human diseases. Therefore, an integral resource of PTM–disease associations （PDAs）would be a great help for both academic research and clinical use. In this work, we reported PTMD,a well-curated database containing PTMs that are associated with human diseases. We manually collected 1950 known PDAs in 749 proteins for 23 types of PTMs and 275 types of diseases from the literature. Database analyses show that phosphorylation has the largest number of disease associations, whereas neurologic diseases have the largest number of PTM associations. We classified all known PDAs into six classes according to the PTM status in diseases and demonstrated that the upregulation and presence of PTM events account for a predominant proportion of diseaseassociated PTM events. By reconstructing a disease–gene network, we observed that breast cancers have the largest number of associated PTMs and AKT1 has the largest number of PTMs connected to diseases. Finally, the PTMD database was developed with detailed annotations and can be a useful resource for further analyzing the relations between PTMs and human diseases. PTMD is freely accessible at http：//***.

关键词： Posttranslational modification Phosphorylation PTM-disease association Disease-gene network AKT1

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Computational strategies to search structured rnas in genomic sequence(and roads towards further analysis)

Computational strategies to search structured RNAs in genomi...

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2011国际基因组学大会

作者： Jan Gorodkin Center for non-coding RNA in Technology and Health IBHVUniversity of CopenhagenDenmark

A key application of early methods for computational rna folding was to aid interpretation of structure probing *** the years computational rna biology has developed in which improved energy models and the availability of multiple genomes have contributed substantially to the development of the *** methods that search for common rna structures in a set of co-regulated rnas have

关键词： rna and roads towards further analysis Computational strategies to search structured rnas in genomic sequence

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Using GPU to accelerate the pairwise structural rna alignment with base pair probabilities

Using GPU to accelerate the pairwise structural RNA alignmen...

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作者： Sundfeld, Daniel Teodoro, George Havgaard, Jakob H. Gorodkin, Jan Melo, Alba C. M. A. Information and Communication Technology Brasília Federal Institute Brasília Brazil Department of Computer Science University of Brasília Brasília Brazil Center for Non-Coding RNA in Technology and Health Department of Veterinary and Animal Sciences University of Copenhagen Copenhagen Denmark

Structural alignments of Ribonucleic acid (rna) sequences solved by the Sankoff algorithm are computationally expensive and often require constraints to be used in practice. Modern Graphics Processing Units (GPUs) contain more than 1000 cores, which compute in parallel to speed up applications. Here, we present a GPU-based solution to the rna structural alignment problem that makes use of precalculated base pair probabilities on the individual sequences. We designed and developed an unconstrained version of the Sankoff algorithm, obtaining the optimal result and calculating the entire four-dimension dynamic programming matrix (4D DP). Our approach uses a two-level wavefront strategy to exploit parallelism. The 4D DP matrix is divided in one external matrix (EM) and several internal matrices (IM). We applied wavefront strategies on the EM and IMs in a two-level hierarchical way. At the first level, the wavefront is applied to the EM, calculating the cells that belong to the same diagonal in parallel. In the second level, since each cell in the EM is itself an IM matrix, the cells that belong to the same IM diagonal are calculated in parallel. The results obtained with real rna sequences show that our GPU version is capable of outperforming a multicore CPU version of the unconstrained version of the Sankoff algorithm. Compared with the CPU-based version running on 32 cores, our approach is able to achieve a speedup of 7.81x on the NVidia Tesla P100. In this case, the execution time was reduced from 6 hours and 18 minutes (32 cores) to 48 minutes and 20 seconds (GPU). © 2019 John Wiley & Sons, Ltd.

关键词： Graphics processing unit

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Computational Discovery of Conserved rna Structures and Functional Characterization of a Structured lncrna in Leishmania braziliensis

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non-coding rna Research 2025年

作者： Caroline R. Espada Christian Anthon Rubens D.M. Magalhães José Carlos Quilles Junior Natalia M.M. Teles Fabiano S. Pais Lissur A. Orsine Letícia de Almeida Tânia P.A. Defina Adam Dowle Jan Gorodkin Pegine B. Walrad Angela K. Cruz Department of Cell and Molecular Biology Ribeirão Preto Medical School University of São Paulo FMRP-USP Ribeirão Preto São Paulo Brasil Department of Biology York Biomedical Research Institute University of York York United Kingdom Center for non-coding RNA in Technology and Health Department of Animal and Veterinary Sciences Faculty for Health and Medical Sciences University of Copenhagen Copenhagen Denmark Data Science Lab Metabolomics and Proteomics Lab Bioscience Technology Facility Department of Biology University of York York United Kingdom

Leishmania parasites alternate between hosts, facing environmental changes that demand rapid gene expression adaptation. Lacking canonical rna polymerase II promoters, transcription in these eukaryotes is polycistronic, with gene regulation occurring post-transcriptionally. Although non-coding rnas (ncrnas) have been identified in Leishmania transcriptomes, their functions remain unclear. Recognizing rna structure's importance, we performed a genome-wide alignment of L. braziliensis and related species, identifying conserved rna structures, 38 of which overlap with known ncrnas. One such ncrna, lncrna45 , was functionally characterized. Using a knockout cell line, we demonstrated that lncrna45 is crucial for parasite fitness. Reintroducing the wild type lncrna45 restored fitness, while a version with a single nucleotide substitution in the structured region did not. This mutation also altered rna-protein interactions. These findings suggest that lncrna45 's regulatory role and protein interactions rely on its secondary structure. This study highlights the significance of structured lncrnas in Leishmania biology and their potential as therapeutic targets. Further research into these ncrnas could uncover new parasite regulation mechanisms and inspire novel treatment strategies.

关键词： non-coding rnas Leishmania braziliensis rna structure Gene expression regulation CRISPR- Cas9

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50 shades of rule composition from chemical reactions to higher levels of abstraction

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Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics) 2014年 8738卷 115-135页

作者： Andersen, Jakob Lykke Flamm, Christoph Merkle, Daniel Stadler, Peter F. Department of Mathematics and Computer Science University of Southern Denmark Denmark Institute for Theoretical Chemistry University of Vienna Austria Bioinformatics Group Department of Computer Science and Interdisciplinary Center for Bioinformatics Leipzig Germany Max Planck Institute for Mathematics in the Sciences Leipzig Germany Fraunhofer Institute for Cell Therapy and Immunology Leipzig Germany Center for Non-coding RNA in Technology and Health University of Copenhagen Denmark Santa Fe Institute United States

ISBN: (纸本)9783319103976

Graph rewriting has been applied quite successfully to model chemical and biological systems at different levels of abstraction. A particularly powerful feature of rule-based models that are rigorously grounded in category theory, is, that they admit a well-defined notion of rule composition, hence, provide their users with an intrinsic mechanism for compressing trajectories and coarse grained representations of dynamical aspects. The same formal framework, however, also allows the detailed analysis of transitions in which the final and initial states are known, but the detailed stepwise mechanism remains hidden. To demonstrate the general principle we consider here how rule composition is used to determine accurate atom maps for complex enzyme reactions. This problem not only exemplifies the paradigm but is also of considerable practical importance for many down-stream analyses of metabolic networks and it is a necessary prerequisite for predicting atom traces for the analysis of isotope labelling experiments. © Springer International Publishing Switzerland 2014.

关键词： Biological systems

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Identification of valid reference genes for microrna expression studies in a hepatitis B virus replicating liver cell line

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BMC Research Notes 2016年第1期9卷 1-7页

作者： Jacobsen, Kari Stougaard Nielsen, Kirstine Overgaard Winther, Thilde Nordmann Glebe, Dieter Pociot, Flemming Hogh, Birthe Department of Paediatrics Hvidovre Hospital University of Copenhagen Copenhagen Denmark Department of Paediatrics Center for Non-Coding RNA in Technology and Health Herlev Hospital University of Copenhagen Copenhagen Denmark Institute of Medical Virology National Reference Center for Hepatitis B and D Viruses German Center for Infection Research Biomedical Research Center Seltersberg Justus-Liebig University Giessen Giessen Germany

Background: Micrornas are regulatory molecules and suggested as non-invasive biomarkers for molecular diagnostics and prognostics. Altered expression levels of specific micrornas are associated with hepatitis B virus infection and hepatocellular carcinoma. We previously identified differentially expressed micrornas with liver-specific target genes in plasma from children with chronic hepatitis B. To further understand the biological role of these micrornas in the pathogenesis of chronic hepatitis B, we have used the human liver cell line HepG2, with and without HBV replication, after transfection of hepatitis B virus expression vectors. RT-qPCR is the preferred method for microrna studies, and a careful normalisation strategy, verifying the optimal set of reference genes, is decisive for correctly evaluating microrna expression levels. The aim of this study was to provide valid reference genes for the human HCC-derived cell line HepG2. Results: A panel of 739 micrornas was screened to identify the most stably expressed micrornas, followed by a PubMed search identifying micrornas previously used as reference genes. Sixteen candidate reference genes were validated by RT-qPCR. Reference gene stabilities were calculated first by standard deviations of ΔCt values and then by geNorm and NormFinder analyses, taking into account the amplification efficiency of each microrna primer set. The optimal set of reference genes was verified by a target analysis using RT-qPCR on miR-215-5p. Conclusion: We identified miR-24-3p, miR-151a-5p, and miR-425-5p as the most valid combination of reference genes for microrna RT-qPCR studies in our hepatitis B virus replicating HepG2 cell model. © 2016 Jacobsen et al.

关键词： Hepatitis B virus microrna Normalisation Reference genes RT-qPCR

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Comparative ncrna gene and structure prediction using foldalign and foldalignM

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Current Protocols in Bioinformatics 2012年第SUPPL.39期39卷

作者： Havgaard, Jakob Kaur, Simranjeet Gorodkin, Jan Center for Non-Coding RNA in Technology and Health Department of Veterinary Clinical and Animal Sciences University of Copenhagen Copenhagen Denmark

This unit describes how to use Foldalign and FoldalignM to make structural alignments of non-protein-coding-rna (ncrna). These tools can be used to find new ncrnas, to find the structure of novel ncrnas, and to improv... 详细信息

关键词： ncrna ncrna gene finding non-coding rna rna multiple sequence alignment rna structural alignment rna structure prediction

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Methane and Co2 Consumption from a Synthetic Waste Gas by Microbial Communities in Enriched Seawater

SSRN

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SSRN 2024年

作者： Frigaard, Niels-Ulrik Seemann, Stefan E. Marine Biological Section Department of Biology University of Copenhagen Helsingør Denmark Center for non-coding RNA in Technology and Health Department of Veterinary and Animal Sciences University of Copenhagen Frederiksberg Denmark

Methane (CH4) and carbon dioxide (CO2) occur as undesirable waste products in carbon-based fuel productions. Bothgases are major greenhouse gases with CH4 being much more potent than CO2. For this reason, excess CH4 from varioussources is often flared into CO2 rather than releasing the CH4 into the atmosphere, however, some CH4 is still emitteddue to the inefficiency of flare combustion. We have explored how natural microbial communities can be manipulatedinto consuming both CH4 and CO2 from a gas stream and converting the gases into microbial biomass. Natural seawaterwas enriched with inorganic nutrients and injected with a continuous gas stream containing CH4 (4.7% v/v) and CO2(1% v/v) over a period of several days, either in the dark or in the light. Microbial communities established thatcontained methanotrophic bacteria consuming CH4, and cyanobacteria and microalgae consuming CO2. The measureof chemotaxonomic markers revealed that the growth of phototrophs increased greatly only in the light with an earlydominance by cyanobacteria later overtaken by microalgae, and that the growth of methanotrophs increased greatlyonly in the dark. The microbial communities were characterized using near-full-length 16S/18S rrna gene ampliconsequencing with the Nanopore technology. In the incubated cultures, the microbial diversity was drastically lower ascompared to the natural communities. The most abundant microalgae were green algae belonging to Picochlorum,Tetraselmis, Chlamydomonas, and Nannochloris, and the most abundant cyanobacteria were related to Geitlerinemasp. PCC 7105, Symphothece sp. PCC 7002 and Cyanobium sp. PCC 6307 (based on the SILVA reference database).Methylomicrobium and Methylobacter were the most abundant methanotrophs in the dark-incubated cultures, whereasMethylomonas methanica was identified as the single methanotroph with notable abundance under light ***, for optimal CH4 and CO2 consumption it may be necessary to physically separate

关键词： Microalgae

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